Abstract Type 1 diabetes complications cause substantial morbidity and mortality. In particular, kidney disease is common, may progress to end stage renal disease, and potently amplifies the risk of cardiovascular disease, the major cause of death in this population. Impaired vitamin D metabolism may contribute to kidney and cardiovascular disease through mechanisms of specific importance to type 1 diabetes. However, the clinical relevance of impaired vitamin D metabolism in type 1 diabetes complications remains to be determined. The overall goal of this application is to assess the potential role of impaired vitamin D metabolism in the pathogenesis of clinically important type 1 diabetes complications. We propose to comprehensively characterize vitamin D metabolism in 1,093 participants in the Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) using a combination of key vitamin D metabolites measured using novel, precise, and accurate mass spectrometry methods. Specifically, we propose to measure 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25- dihydroxyvitamin D to ascertain vitamin D intake, turnover, and activity, respectively. We will relate these measurements to an extensive collection of pathway-appropriate clinical microvascular and macrovascular disease outcomes collected by DCCT/EDIC over long-term follow-up. We will test the hypotheses that impaired vitamin D metabolism (lower 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations) is associated with the development of diabetic kidney disease and subclinical cardiovascular disease. To successfully complete the proposed aims, we have assembled a multidisciplinary team of investigators with long-standing direct involvement in DCCT/EDIC who have substantial expertise in type 1 diabetes and its complications, vitamin D metabolism, laboratory science, epidemiology, and biostatistics. PUBLIC HEALTH RELEVANCE: Narrative Novel therapeutic targets are needed to prevent the development of type 1 diabetes complications, which continue to occur at high rates despite the application of existing therapies. The proposed studies will help determine the extent to which impaired vitamin D metabolism is a therapeutic target for the prevention of kidney and cardiovascular disease in type 1 diabetes. These studies will focus on the high-risk type 1 diabetes population;better define the components of impaired vitamin D metabolism most strongly related to adverse health outcomes by using a combination of novel and precise biomarkers;establish temporal relationships of impaired vitamin D metabolism with kidney disease and mechanisms through which impaired vitamin D metabolism may increase cardiovascular risk;and build a critical foundation of knowledge for the design of clinical trials targeting impaired vitamin D metabolism.